Cytokines exert their respective biochemical and physiological effects by binding to specific receptor molecules. Receptor binding then stimulates specific signal transduction pathways (Kishimoto et al., Cell 76:253-262, 1994). The specific interactions of cytokines with their receptors can be the primary regulators of a wide variety of cellular processes including activation, proliferation, and differentiation of cells (Arai et al., Ann. Rev. Biochem. 59:783-836, 1990; Paul and Seder, Cell 76:241-251, 1994).
Interleukin-21 (IL-21) is a type I cytokine whose receptor is expressed on T, B, and NK cells. IL-21 was isolated from a cDNA library derived from activated CD3 (+) T cells (Parrish-Novak et al., Nature 408 57-63, 2000). The IL-21 cDNA encodes a secreted protein of 131 amino acids protein most closely related to IL-2 and IL-15. The IL-21 gene has been mapped to human chromosome 4q26-q27 near the IL-2 gene.
IL-21 mRNA is expressed in activated CD4+ but not in activated CD8+ T cells. In addition, IL-21 expression was not detected in B cells and monocytes (Parrish-Novak et al., Nature 408:57-63, 2000). IL-21 has also been shown to stimulate proliferation of naïve (CD45RA+) cells, but not memory (CD45RO+) T cells, mediated by engagement of CD3. IL-21 has also been shown to stimulate the proliferation of bone marrow progenitor to cells and to enhance the expression of the NK-cell marker CD56 in the presence of IL-15 (for review, see Horst Ibelgaufts' COPE: Cytokines Online Pathfinder Encyclopedia, available on the internet). In vitro, IL-21 can act as a co-mitogen for anti-CD3-induced thymocyte and peripheral T cell proliferation (Parrish-Novak et al., Nature 408:57-63, 2000), augment NK cell expansion and differentiation from human CD34+ cells when cultured with IL-15 and Flt-3 ligand, and can also activate NK-cytolytic activity (Parrish-Novak et al., Nature 408:57-63, 2000; Kasaian et al., Immunity 16:559, 2002).
The IL-21 receptor has been isolated and was found to be expressed by CD23+ B cells, B cell lines, a T cell leukemia line, and NK cell lines. The receptor gene has been mapped to human chromosome 16p12 (see Parrish-Novak et al., Nature 408:57-63, 2000; Ozaki et al., Proc. Natl. Acad. Sci. USA 97:11439-11444, 2000). The receptor (538 amino acids) is most closely related to human IL-2 receptor beta chain, and contains a WSXWS (SEQ ID NO: 17) motif in the extracellular region, typical of type-1 cytokine receptors (see Ozaki et al., Proc. Natl. Acad. Sci. USA 97:11439-11444, 2000; Parrish-Novak et al., Nature 408:57-63, 2000; and Nat. Rev. Immunol. 1:200-208). The common cytokine receptor gamma chain, an indispensable subunit of the functional receptor complexes for IL-2, IL-4, IL-7, IL-9, and IL-15 has been shown also to be part of the IL-21 receptor complex. The functional signaling complex signals in part through the activation of Jak1 and Jak3 as well as Stat1, Stat3, and Stat5 (see Asao et al., J. Immunol. 167:1-5, 2000; Ozaki et al., Proc. Natl. Acad. Sci. USA 97:11439-11444, 2000). However, the specific effects of IL-21 on the differentiation and populations of B cells and the activity of specific B cell populations have not previously been elucidated.